Scientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’
The Centre for Addiction and Mental Health
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Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.
EurekAlert
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A research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter.
EurekAlert
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Scientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’
BBC
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A race to unlock genetic clues behind living to 100 is set to begin next year, after a US team announced it will compete for the $10m Genomics X Prize. Genetic entrepreneur Dr Jonathan Rothberg is entering the challenge to identify genes linked to a long, healthy life. His team – and any other contenders – will be given 30 days to work out the full DNA code of 100 centenarians at a cost of no more than $1,000 per genome.
The race will start in September 2013. Under the rules of the Archon Genomics X Prize, teams have until next May to register for the competition. Dr Rothberg’s team from Life Technologies Corporation in California is the first to formally enter the race.
His latest business venture, Ion Torrent, makes the Personal Genome Machine and the Ion Proton sequencer
Rothberg claims his machines can sequence DNA more quickly and cheaply than ever thought possible
The Ion Proton sequencer will be used for the challenge. Being able to sequence the full human genome at a cost of $1,000 or less is regarded as a milestone in science.
It is seen as the threshold at which DNA sequencing technology becomes cheap enough to be used widely in medicine, helping in diagnosis and in matching drugs to a patient’s genetic make-up.
‘
One hundred people aged 100 have donated their DNA for the project.
Scientists believe people who reach a very old age may have certain rare changes in their genes which protect against common diseases of later life, such as heart disease and cancer. If these genes can be identified by analysing the DNA codes of centenarians, it will help scientists search for new medical treatments and perhaps ways to prolong life. However, many sample DNA sequences will be needed in order to get the accuracy needed to pinpoint changes on the scale of a few genetic letters among the three billion in the human genome.
Dr Jonathan Rothberg, a geneticist and entrepreneur, said the DNA of 100 centenarians is a good start towards finding ‘the fountains of youth’.
He told BBC News: ‘One hundred people will give you a hint. One thousand will make you reasonably sure. Ten thousand will let you say, ‘Hey, these are the genes involved in cancer or heart disease”.
Dr Craig Venter is the originator of the prize and one of the main players in the race to sequence the first human genome, which was completed in 2003.
BBC
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The hormone oxytocin—often referred to as the ‘trust’ hormone or ‘love hormone’ for its role in stimulating emotional responses—plays an important role in Williams syndrome (WS), according to a study.
The study, a collaboration between scientists at the Salk Institute for Biological Studies and the University of Utah, found that people with WS flushed with the hormones oxytocin and arginine vasopressin (AVP) when exposed to emotional triggers.
The findings may help in understanding human emotional and behavioural systems and lead to new treatments for devastating illnesses such as WS, post-traumatic stress disorder, anxiety and possibly even autism.
‘Williams syndrome results from a very clear genetic deletion, allowing us to explore the genetic and neuronal basis of social behaviour,’ says Ursula Bellugi, the director of Salk’s Laboratory for Cognitive Neuroscience and a co-author on the paper. ‘This study provides us with crucial information about genes and brain regions involved in the control of oxytocin and vasopressin, hormones that may play important roles in other disorders.’
WS arises from a faulty recombination event during the development of sperm or egg cells. As a result, virtually everyone with WS has exactly the same set of genes missing (25 to 28 genes are missing from one of two copies of chromosome 7). There also are rare cases of individuals who retain one or more genes that most people with the disorder have lost.
To children with WS, people are much more comprehensible than inanimate objects. Despite myriad health problems they are extremely gregarious, irresistibly drawn to strangers, and insist on making eye contact. They have an affinity for music. But they also experience heightened anxiety, have an average IQ of 60, experience severe spatial-visual problems, and suffer from cardiovascular and other health issues. Despite their desire to befriend people, they have difficulty creating and maintaining social relationships, something that is not at all understood but can afflict many people without WS.
In the new study, led by Dr. Julie R. Korenberg, a University of Utah professor and Salk adjunct professor, the scientists conducted a trial with 21 participants, 13 who have WS and a control group of eight people without the disorder. The participants were evaluated at the Cedars-Sinai Medical Center in Los Angeles. Because music is a known strong emotional stimulus, the researchers asked participants to listen to music.
Before the music was played, the participants’ blood was drawn to determine a baseline level for oxytocin, and those with WS had three times as much of the hormone as those without the syndrome. Blood also was drawn at regular intervals while the music played and was analysed afterward to check for real-time, rapid changes in the levels of oxytocin and AVP. Other studies have examined how oxytocin affects emotion when artificially introduced into people, such as through nasal sprays, but this is one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real time as people undergo an emotional response.
There was little outward response to the music, but when the blood samples were analysed, the researchers were happily surprised. The analyses showed that the oxytocin levels, and to a lesser degree AVP, had not only increased but begun to bounce among WS participants while among those without WS, both the oxytocin and AVP levels remained largely unchanged as they listened to music.
Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with WS, and that the behavioural characteristics unique to people with WS are related to this problem.
‘This shows that oxytocin quite likely is very involved in emotional response,’ Korenberg says.
To ensure accuracy of results, those taking the test also were asked to place their hands in 60-degree Fahrenheit water to test for negative stress, and the same results were produced as when they listened to music. Those with WS experienced an increase in oxytocin and AVP, while those without the syndrome did not.
Salk Institute
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A new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumour growth and offer a new way to treat the disease.
The animal study was led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumours that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.
When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumours, with tumours making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.
‘These findings reveal that miR-122 has a critical tumour-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer,’ says study leader Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC – James Experimental Therapeutics Program.
More than 28,700 new cases of HCC are expected in the United States in 2012, and 20,550 Americans are expected to die of the malignancy. Major risk factors for HCC include hepatitis B and C virus infection and liver damage due to alcohol use. HCC is curable if caught early, but most cases are diagnosed at a late, incurable stage.
MiR-122 is found mainly in liver cells – it is the most abundant microRNA in those cells – and it plays a major role in regulating cholesterol in the body. This microRNA is lost in some people with HCC, however, resulting in a poor prognosis.
For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.
The researchers then used a second strain of mice that spontaneously develops liver cancer due to over-expression of a cancer-causing gene called MYC (pronounced ‘mick’). The researchers delivered miR-122 into the animals’ livers during tumour development. Three weeks later, those treated with the molecule had smaller and fewer tumours.
‘The model we developed for these studies will not only facilitate our understanding of liver biology but also be good for testing therapeutic efficacy of newly developed drugs against liver disease, including HCC,’ Ghoshal says.
Ghoshal also notes that research by others has shown that hepatitis C virus requires miR-122 for replication. ‘Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,’ she says.
The Ohio State University Comprehensive Cancer Center
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Severe influenza doubles the odds that a person will develop Parkinson’s disease later in life, according to University of British Columbia researchers.
However, the opposite is true for people who contracted a typical case of red measles as children – they are 35 per cent less likely to develop Parkinson’s, a nervous system disorder marked by slowness of movement, shaking, stiffness, and in the later stages, loss of balance.
The findings by researchers at UBC’s School of Population and Public Health and the Pacific Parkinson’s Research Centre are based on interviews with 403 Parkinson’s patients and 405 healthy people in British Columbia, Canada.
Lead author Anne Harris also examined whether occupational exposure to vibrations – such as operating construction equipment – had any effect on the risk of Parkinson’s. In another study she and her collaborators reported that occupational exposure actually decreased the risk of developing the disease by 33 percent, compared to people whose jobs involved no exposure.
Meanwhile, Harris found that those exposed to high-intensity vibrations – for example, by driving snowmobiles, military tanks or high-speed boats – had a consistently higher risk of developing Parkinson’s than people whose jobs involved lower-intensity vibrations (for example, operating road vehicles). The elevated risk fell short of the statistical significance typically used to establish a correlation, but was strong and consistent enough to suggest an avenue for further study, Harris says.
‘There are no cures or prevention programs for Parkinson’s, in part because we still don’t understand what triggers it in some people and not others,’ says Harris, who conducted the research while earning her doctorate at UBC. ‘This kind of painstaking epidemiological detective work is crucial in identifying the mechanisms that might be at work, allowing the development of effective prevention strategies.’
University of British Columbia
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Researchers at Case Western Reserve University School of Medicine have uncovered the first molecular evidence linking the body’s natural circadian rhythms to sudden cardiac death.
Mukesh K. Jain, MD, Darwin Jeyaraj, MD, and colleagues discovered a genetic factor called Kruppel-like Factor 15—or KLF15—that links the body’s natural clock to the heart’s electrical activity system. Too much or too little KLF15 causes a disruption in the heart’s electrical activity, greatly increasing susceptibility to arrhythmias.
These abnormal heart rhythms, which are the most common cause of sudden cardiac death, occur most frequently in the morning and evening. While scientists have been aware of these patterns in the heart’s electrical stability for years, this discovery provides insight into the biological mechanism behind the variations and suggests therapies that modulate the biological clock could be beneficial in preventing sudden cardiac death.
Case Western Reserve University
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Researchers at Case Western Reserve University School of Medicine have discovered a mutant form of the gene, Chk1, that when expressed in cancer cells, permanently stopped their proliferation and caused cell death without the addition of any chemotherapeutic drugs. This study illustrates an unprecedented finding, that artificially activating Chk1 alone is sufficient to kill cancer cells.
‘We have identified a new direction for cancer therapy and the new direction is leading us to a reduction in toxicity in cancer therapy, compared with chemotherapy or radiation therapy,’ said Dr. Zhang, assistant professor, Department of Pharmacology at the School of Medicine, and member of the university’s Case Comprehensive Cancer Center. ‘With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.’
While studying the basic mechanisms for genome integrity, Dr. Zhang’s team unexpectedly discovered an active mutant form of human Chk1, which is also a non-natural form of this gene. This mutation changed the protein conformation of Chk1 from the inactive form into an active form. Remarkably, the research team discovered that when expressed in cancer cells, this active mutant form of Chk1 permanently stopped cancer cell proliferation and caused cell death in petri dishes even without the addition of any chemotherapeutic drugs.
The biggest advantage of this potential strategy is that no toxic chemotherapeutic drug is needed to achieve the same cancer killing effect used with a combination of Chk1 inhibitors and chemotherapeutic drugs.
Cells respond to DNA damage by activating networks of signalling pathways, termed cell cycle checkpoints. Central to these genome pathways is the protein kinase, called Chk1. Chk1 facilitates cell survival, including cancer cells, under stressful conditions, such as those induced by chemotherapeutic agents, by placing a temporary stop on the cell cycle progression and co-ordinating repair programs to fix the DNA errors.
It has long been suggested that combining Chk1 inhibition with chemotherapy or radiotherapy should significantly enhance the anticancer effect of these therapies. This idea has serves as the basis for multiple pharmaceutical companies searching for potential Chk1 inhibitors that can effectively combine with chemotherapy in cancer therapy. To date, no Chk1 inhibitor has passed the clinical trial stage III . This led Dr. Zhang’s team to look for alternative strategies for targeting Chk1 in cancer therapy.
Future research by Dr. Zhang and his team will consider two possible approaches to artificially activating Chk1 in cancer cells. One possibility is to use the gene therapy concept to deliver the active mutant form of Chk1 that the team discovered, into cancer cells. The other is to search for small molecules that can induce the same conformational change of Chk1, so that they can be delivered into cancer cells to activate Chk1 molecules. The consequence of either would be permanent cell proliferation inhibition and cancer.
EurekAlert
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Genetic link to rapid weight gain from antipsychotics discovered
, /in E-News /by 3wmediaScientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’ The Centre for Addiction and Mental Health
Genetic mutations that cause common childhood brain tumours identified
, /in E-News /by 3wmediaResearchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma. EurekAlert
Genetic markers for testosterone and oestrogen level regulation identified
, /in E-News /by 3wmediaA research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter. EurekAlert
Olympic Team GB trials gene tests for injury
, /in E-News /by 3wmediaScientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’ BBC
Genetic entrepreneur to compete in Genomics X Prize
, /in E-News /by 3wmediaA race to unlock genetic clues behind living to 100 is set to begin next year, after a US team announced it will compete for the $10m Genomics X Prize. Genetic entrepreneur Dr Jonathan Rothberg is entering the challenge to identify genes linked to a long, healthy life. His team – and any other contenders – will be given 30 days to work out the full DNA code of 100 centenarians at a cost of no more than $1,000 per genome.
The race will start in September 2013. Under the rules of the Archon Genomics X Prize, teams have until next May to register for the competition. Dr Rothberg’s team from Life Technologies Corporation in California is the first to formally enter the race.
His latest business venture, Ion Torrent, makes the Personal Genome Machine and the Ion Proton sequencer
Rothberg claims his machines can sequence DNA more quickly and cheaply than ever thought possible
The Ion Proton sequencer will be used for the challenge. Being able to sequence the full human genome at a cost of $1,000 or less is regarded as a milestone in science.
It is seen as the threshold at which DNA sequencing technology becomes cheap enough to be used widely in medicine, helping in diagnosis and in matching drugs to a patient’s genetic make-up.
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One hundred people aged 100 have donated their DNA for the project.
Scientists believe people who reach a very old age may have certain rare changes in their genes which protect against common diseases of later life, such as heart disease and cancer. If these genes can be identified by analysing the DNA codes of centenarians, it will help scientists search for new medical treatments and perhaps ways to prolong life. However, many sample DNA sequences will be needed in order to get the accuracy needed to pinpoint changes on the scale of a few genetic letters among the three billion in the human genome.
Dr Jonathan Rothberg, a geneticist and entrepreneur, said the DNA of 100 centenarians is a good start towards finding ‘the fountains of youth’.
He told BBC News: ‘One hundred people will give you a hint. One thousand will make you reasonably sure. Ten thousand will let you say, ‘Hey, these are the genes involved in cancer or heart disease”.
Dr Craig Venter is the originator of the prize and one of the main players in the race to sequence the first human genome, which was completed in 2003. BBC
‘Trust’ hormone oxytocin found at heart of rare genetic disorder
, /in E-News /by 3wmediaThe hormone oxytocin—often referred to as the ‘trust’ hormone or ‘love hormone’ for its role in stimulating emotional responses—plays an important role in Williams syndrome (WS), according to a study.
The study, a collaboration between scientists at the Salk Institute for Biological Studies and the University of Utah, found that people with WS flushed with the hormones oxytocin and arginine vasopressin (AVP) when exposed to emotional triggers.
The findings may help in understanding human emotional and behavioural systems and lead to new treatments for devastating illnesses such as WS, post-traumatic stress disorder, anxiety and possibly even autism.
‘Williams syndrome results from a very clear genetic deletion, allowing us to explore the genetic and neuronal basis of social behaviour,’ says Ursula Bellugi, the director of Salk’s Laboratory for Cognitive Neuroscience and a co-author on the paper. ‘This study provides us with crucial information about genes and brain regions involved in the control of oxytocin and vasopressin, hormones that may play important roles in other disorders.’
WS arises from a faulty recombination event during the development of sperm or egg cells. As a result, virtually everyone with WS has exactly the same set of genes missing (25 to 28 genes are missing from one of two copies of chromosome 7). There also are rare cases of individuals who retain one or more genes that most people with the disorder have lost.
To children with WS, people are much more comprehensible than inanimate objects. Despite myriad health problems they are extremely gregarious, irresistibly drawn to strangers, and insist on making eye contact. They have an affinity for music. But they also experience heightened anxiety, have an average IQ of 60, experience severe spatial-visual problems, and suffer from cardiovascular and other health issues. Despite their desire to befriend people, they have difficulty creating and maintaining social relationships, something that is not at all understood but can afflict many people without WS.
In the new study, led by Dr. Julie R. Korenberg, a University of Utah professor and Salk adjunct professor, the scientists conducted a trial with 21 participants, 13 who have WS and a control group of eight people without the disorder. The participants were evaluated at the Cedars-Sinai Medical Center in Los Angeles. Because music is a known strong emotional stimulus, the researchers asked participants to listen to music.
Before the music was played, the participants’ blood was drawn to determine a baseline level for oxytocin, and those with WS had three times as much of the hormone as those without the syndrome. Blood also was drawn at regular intervals while the music played and was analysed afterward to check for real-time, rapid changes in the levels of oxytocin and AVP. Other studies have examined how oxytocin affects emotion when artificially introduced into people, such as through nasal sprays, but this is one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real time as people undergo an emotional response.
There was little outward response to the music, but when the blood samples were analysed, the researchers were happily surprised. The analyses showed that the oxytocin levels, and to a lesser degree AVP, had not only increased but begun to bounce among WS participants while among those without WS, both the oxytocin and AVP levels remained largely unchanged as they listened to music.
Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with WS, and that the behavioural characteristics unique to people with WS are related to this problem.
‘This shows that oxytocin quite likely is very involved in emotional response,’ Korenberg says.
To ensure accuracy of results, those taking the test also were asked to place their hands in 60-degree Fahrenheit water to test for negative stress, and the same results were produced as when they listened to music. Those with WS experienced an increase in oxytocin and AVP, while those without the syndrome did not. Salk Institute
Loss of a tiny liver molecule might lead to liver cancer
, /in E-News /by 3wmediaA new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumour growth and offer a new way to treat the disease.
The animal study was led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumours that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.
When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumours, with tumours making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.
‘These findings reveal that miR-122 has a critical tumour-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer,’ says study leader Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC – James Experimental Therapeutics Program.
More than 28,700 new cases of HCC are expected in the United States in 2012, and 20,550 Americans are expected to die of the malignancy. Major risk factors for HCC include hepatitis B and C virus infection and liver damage due to alcohol use. HCC is curable if caught early, but most cases are diagnosed at a late, incurable stage.
MiR-122 is found mainly in liver cells – it is the most abundant microRNA in those cells – and it plays a major role in regulating cholesterol in the body. This microRNA is lost in some people with HCC, however, resulting in a poor prognosis.
For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.
The researchers then used a second strain of mice that spontaneously develops liver cancer due to over-expression of a cancer-causing gene called MYC (pronounced ‘mick’). The researchers delivered miR-122 into the animals’ livers during tumour development. Three weeks later, those treated with the molecule had smaller and fewer tumours.
‘The model we developed for these studies will not only facilitate our understanding of liver biology but also be good for testing therapeutic efficacy of newly developed drugs against liver disease, including HCC,’ Ghoshal says.
Ghoshal also notes that research by others has shown that hepatitis C virus requires miR-122 for replication. ‘Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,’ she says. The Ohio State University Comprehensive Cancer Center
Severe flu increases risk of Parkinson’s: UBC research
, /in E-News /by 3wmediaSevere influenza doubles the odds that a person will develop Parkinson’s disease later in life, according to University of British Columbia researchers.
However, the opposite is true for people who contracted a typical case of red measles as children – they are 35 per cent less likely to develop Parkinson’s, a nervous system disorder marked by slowness of movement, shaking, stiffness, and in the later stages, loss of balance.
The findings by researchers at UBC’s School of Population and Public Health and the Pacific Parkinson’s Research Centre are based on interviews with 403 Parkinson’s patients and 405 healthy people in British Columbia, Canada.
Lead author Anne Harris also examined whether occupational exposure to vibrations – such as operating construction equipment – had any effect on the risk of Parkinson’s. In another study she and her collaborators reported that occupational exposure actually decreased the risk of developing the disease by 33 percent, compared to people whose jobs involved no exposure.
Meanwhile, Harris found that those exposed to high-intensity vibrations – for example, by driving snowmobiles, military tanks or high-speed boats – had a consistently higher risk of developing Parkinson’s than people whose jobs involved lower-intensity vibrations (for example, operating road vehicles). The elevated risk fell short of the statistical significance typically used to establish a correlation, but was strong and consistent enough to suggest an avenue for further study, Harris says.
‘There are no cures or prevention programs for Parkinson’s, in part because we still don’t understand what triggers it in some people and not others,’ says Harris, who conducted the research while earning her doctorate at UBC. ‘This kind of painstaking epidemiological detective work is crucial in identifying the mechanisms that might be at work, allowing the development of effective prevention strategies.’ University of British Columbia
Circadian rhythms and the heart
, /in E-News /by 3wmediaResearchers at Case Western Reserve University School of Medicine have uncovered the first molecular evidence linking the body’s natural circadian rhythms to sudden cardiac death.
Mukesh K. Jain, MD, Darwin Jeyaraj, MD, and colleagues discovered a genetic factor called Kruppel-like Factor 15—or KLF15—that links the body’s natural clock to the heart’s electrical activity system. Too much or too little KLF15 causes a disruption in the heart’s electrical activity, greatly increasing susceptibility to arrhythmias.
These abnormal heart rhythms, which are the most common cause of sudden cardiac death, occur most frequently in the morning and evening. While scientists have been aware of these patterns in the heart’s electrical stability for years, this discovery provides insight into the biological mechanism behind the variations and suggests therapies that modulate the biological clock could be beneficial in preventing sudden cardiac death. Case Western Reserve University
Researchers discover gene that permanently stops cancer cell proliferation
, /in E-News /by 3wmediaResearchers at Case Western Reserve University School of Medicine have discovered a mutant form of the gene, Chk1, that when expressed in cancer cells, permanently stopped their proliferation and caused cell death without the addition of any chemotherapeutic drugs. This study illustrates an unprecedented finding, that artificially activating Chk1 alone is sufficient to kill cancer cells.
‘We have identified a new direction for cancer therapy and the new direction is leading us to a reduction in toxicity in cancer therapy, compared with chemotherapy or radiation therapy,’ said Dr. Zhang, assistant professor, Department of Pharmacology at the School of Medicine, and member of the university’s Case Comprehensive Cancer Center. ‘With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.’
While studying the basic mechanisms for genome integrity, Dr. Zhang’s team unexpectedly discovered an active mutant form of human Chk1, which is also a non-natural form of this gene. This mutation changed the protein conformation of Chk1 from the inactive form into an active form. Remarkably, the research team discovered that when expressed in cancer cells, this active mutant form of Chk1 permanently stopped cancer cell proliferation and caused cell death in petri dishes even without the addition of any chemotherapeutic drugs.
The biggest advantage of this potential strategy is that no toxic chemotherapeutic drug is needed to achieve the same cancer killing effect used with a combination of Chk1 inhibitors and chemotherapeutic drugs.
Cells respond to DNA damage by activating networks of signalling pathways, termed cell cycle checkpoints. Central to these genome pathways is the protein kinase, called Chk1. Chk1 facilitates cell survival, including cancer cells, under stressful conditions, such as those induced by chemotherapeutic agents, by placing a temporary stop on the cell cycle progression and co-ordinating repair programs to fix the DNA errors.
It has long been suggested that combining Chk1 inhibition with chemotherapy or radiotherapy should significantly enhance the anticancer effect of these therapies. This idea has serves as the basis for multiple pharmaceutical companies searching for potential Chk1 inhibitors that can effectively combine with chemotherapy in cancer therapy. To date, no Chk1 inhibitor has passed the clinical trial stage III . This led Dr. Zhang’s team to look for alternative strategies for targeting Chk1 in cancer therapy.
Future research by Dr. Zhang and his team will consider two possible approaches to artificially activating Chk1 in cancer cells. One possibility is to use the gene therapy concept to deliver the active mutant form of Chk1 that the team discovered, into cancer cells. The other is to search for small molecules that can induce the same conformational change of Chk1, so that they can be delivered into cancer cells to activate Chk1 molecules. The consequence of either would be permanent cell proliferation inhibition and cancer. EurekAlert